Pharmaceutical compositions for intranasal administration of dihydroergotamine

Abstract: A pharmaceutical composition for nasal administration comprising dihydroergotamine and/or a dihydroergotaminesalt and a cyclodextrin and/or an other saccharide and/or a sugar alcohol.

Description: This invention is related to pharmaceutical compositions for nasal administration of dihydroergotamine, and methods of administering such compositions. Dihydroergotamine (DHE) mesylate has been used in migraine therapy already for a long time. In patients with migraine attacks, DHE is suitable for basic interval treatment using tablets or solution, both for oral application, as well as for acute treatment by intravenous or intramuscular injection. DHE has been introduced in a nasal spray to avoid the parenteral and the oral route of administration. The nasal spray seems a good alternative, because it is less painful, less expensive and less inconvenient thank injection therapy. Secondly, nausea and vomiting are common in migraine patients, making a nasal spray much more efficient than oral treatment. A nasal spray containing DHE 4 mg/ml in an aqueous solution has been studied extensively by a number of investigators. Some of these investigators report, that besides DHE the nasal spray also contains glucose 5% and caffeine 1%. It was found that 1 mg of DHE, nasally administered, had the equivalence of 10 mg orally, and almost 40% of the bioavailability of the i.m. administration (PG Andersson and LT Jespersen, Cephalalgia 1986; 6: 51-54). The maximal venoconstrictor effect of 1 mg nasal DHE amounted to about 40%, of 0.5 mg i.m. DHE to about 50% of the initial venous diameter (W.H. Aellig and J.Rosenthaler, Eur. J. Clin. Pharmacol. 1986; 30: 581-584). Nasal DHE appeared to be equally effective than a combination of oral ergotamine and caffeine in relieving migraine attacks (D. Hirt et al. , Cephalalgia 1989; 9. Suppl. 10: 410-411). Another study in 904 patients confirmed the efficacy of nasal DHE and reported side effects in 18.4% of patients: nasal irritation, nausea, vomiting, fatigue, vertigo, breathlessness, tachycardia and perspiration. Only 3.9% of the patients refused further treatment with nasal DHE (G. Jenzer and M.F. Bermgartner, Schweiz. Rundsch. Med. Prax. 1990: 79: 914-917). Lataste et al. (Cephalalgia 1989; 9 suppl. 10: 342-343) and Di Serio et al. (Cephalalgia 1989; 9. suppl. 10:344.345), confirm the efficacy of nasal DHE in the acute management of migraine. In contrast, Tulunayt et al. (Cephalalgia 1987; 7: 131-133) found little difference in nasal DHE and placebo. Most of these studies are very encouraging and therefore nasal DHE, in the pharmaceutical composition studied by the above mentioned authors, seems an interesting alternadve for oral and parenteral DHE preparations. Nasal DHE in the composition of DHE mesylate 4 mg/ml in 5% glucose and 1% caffeine, is available on prescription in several countries (e.g. Switzerland, France, Belgium). Nevertheless, there is an urgent need for another DHE nasal drug formulation, because the nasal preparation, presently on the market, is not stable. It is on the market as a separate glass ampoule (containing the DHE formulation) which has to be broken by the patient and sprayed in the nose using a separate spray device. After opening of the ampoule, the spray can be used no longer than 24 hours. A number of nasal formulations containing ergot alkaloids, including DHE and various excipients, in liquid and powdered form, are described in GB 1592563. Liquid nasal formulations containing DHE and xanthines such as caffeine, are disclosed in US 5169849. The influence excipients, such as hydroxyalkyl derivatives of β-cyclodextrin, have on ciliary movement is reviewed in Hermes and Merkus (Deutsche Apotheker Zeitung 1990; 130; No.44: 2411-2415). EP 0463653 discloses pharmaceutical compositions that include penetration or absorption promoters that have disruptive effects on lipid membranes. These compositions include cydodextrin for the purpose of reducing the disruptive effects on lipid membranes that are produced by the penetration or absorption promoters. Accordingly, it is an object of the invention to provide a highly stable pharmaceutical composition, suitable for nasal administration, capable of introducing efficiently a therapeutical amount of DHE into the human body. It has surprisingly been found that a pharmaceutically acceptable DHE composition can be formulated, suitable for nasal administration, without the presence of a special caffeine-glucose vehicle and without the necessity of presenting the formulation in a separate glass ampoule. In a first aspect, the present invention provides a powdered pharmaceutical composition for nasal administration, comprising DHE, a DHE salt or a combination thereof, and an excipient, wherein the excipient is comprised of cyclodextrin, sugar alcohol or dextran, or any combination thereof, provided that, when a cyclodextrin is present in the pharmaceutical composition, said composition does not indude a penetration or absorption promoter, the disruptive effect of which, on lipid membranes, is reduced in the presence of the cyclodextrin. In a second aspect, the present invention provides a pharmaceutical composition for nasal administration, comprising DHE, a DHE salt or a combination thereof, and an excipient, wherein the excipient is comprised of cyclodextrin, or dextran, or any combination thereof, provided that, when a cydodextrin is present in the pharmaceutical composition, said composition does not include a penetration or absorption promoter, the disruptive effect of which, on lipid membranes, is reduced in the presence of the cyclodextrin. In a third aspect, the present invention provides a pharmaceutical compositions for nasal administration, consisting of DHE, a DHE salt or a combination thereof, and an excipient, wherein the excipient consists of cyclodextrin, sugar alcohol or dextran, or any combination thereof. In a fourth aspect, the present invention provides a pharmaceutical composition for nasal administration, consisting of DHE, a DHE salt or a combination thereof, and an excipient, wherein the excipient consists of cyclodomrin, dextran, or any combination thereof, and optionally sugar alcohol. In embodiments, the nasal pharmaceutical composition can contain DHE and/or a salt of DHE (mesylate or tartrate) and a cyclodextrin and/or other saccharides and/or sugar alcohols.Compositions in accordance with the invention appear to result in a surprisingly high bioavailability and a superior stability of DHE. The term "cyclodextrins" refers to cyclic oligosaccharides, like α-, β- and γ-cyclodextrin and their derivatives, preferably β-cyclodextrin and its derivatives,preferably methylated β-cyclodextrin, with a degree of CH 3 -substitution between 0.5 and 3.0, more preferably between 1.7 and 2.1. The term "saccharides" refers to disaccharides, like lactose, maltose, saccharose and also refers to polysaccharides, like dextrans, with an average molecular weight between 10,000 and 100,000, preferably 40,000 and 70,000. The term "sugar alcohols" refers to mannitol and sorbitol. The nasal composition, according to the invention, can be administered as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. The administration of the nasal composition may also take place using a nasal tampon or nasal sponge, containing the invention composition. In particular, powder formulations show a surprisingly high bioavailability and superior stability of the DHE. In addition, powder formulations have the advantage that no preservatives are necessary. Preservatives are known to decrease the ciliary movement, which may be harmful in chronic nasal medication (Hermens W.A.J.J. and Merkus F.W.H.M., Pharm. Res. 1987; 4: 445-449). Nasal powder compositions can be made by mixing the active agent and the excipient, both possessing the desired particle size. Other methods to make a suitable powder formulation can be selected. Firstly, a solution of the active agent and the cyclodextrin and/or the other saccharide and/or sugar alcohol is made, followed by precipitation, filtration and pulverization. It is also possible to remove the solvent by freeze drying, followed by pulverization of the powder in the desired particle size by using conventional techniques, known from the pharmaceutical literature. The final step is size classification for instance by sieving, to get particles that are less than 100 µm in diameter, preferably between 50 and 100 µm in diameter. Powders can be administered using a nasal insufflator. Powders may also be administered in such a manner that they are placed in a capsule. The capsule is set in an inhalation or insufflation device. A needle is penetrated through the capsule to make pores at the top and the bottom of the capsule and air is sent to blow out the powder particles. Powder formulation can also be administered in a jet-spray of an inert gas or suspended in liquid organic fluids. Also the active agent can be brought into a viscous basis, using vehicles, conventionally used, for example natural gums, methylcellulose and derivatives, acrylic polymers (carbopol) and vinyl polymers (polyvinylpyrrolidone). In the invention compositions many other excipients, known from the pharmaceutical literature, can be added, such as preservatives, surfactants, co-solvents, adhesives, anti-oxidants, buffers, viscosity enhancing agents, and agents to adjust the pH or the osmolarity. The required amount for a nasal administration of a liquid or semi-solid nasal administration form is generally between 0.05 ml and 0.2 ml, preferably about 0.1 ml per nostril. The amount of a powder nasal formulation is generally between 1 and 15 mg, preferably about 5 to 10 mg per nostril. Doses of DHE in the nasal pharmaceutical composition of the invention, suitable in the treatment of migraine attacks, are preferably in the range from 0.25 to 0.5 mg per nostril. The following examples illustrate the invention in more detail: EXAMPLE 1 (liquid) Dihydroergotamine mesylate 250 mg Methyl-β-cyclodextrin D.S. 1.8 2.5 g Benzalkonium Chloride 0.01 % Sodium EDTA 0.05-0.1 % Sorbitol 5 % Purified water to 100 ml 100 µl = 250 µg DHE mesylate EXAMPLE 2 (gel) Dihydroergotamine mesylate 0.5 mg Methyl-β-cyclodextrin D.S. 1.8 5 g Benzalkonium Chloride 0.01 % Sodium EDTA 0.05-0.1 % Sorbitol 5 % Hydroxypropylmethylcellulose 1-2 % Purified water to 100 ml 100 µl = 500 µg DHE mesylate EXAMPLE 3A (powder) Dihydroergotamine mesylate 0.5 mg Methyl-β-cyclodextrin 5 mg Mannitol 4.5 mg 10 mg powder = 500 µg DHE mesylate EXAMPLE 3B (powder) Dihydroergotamine mesylate . 0.5 mg Dextran (average M.W. 70,000) 9.5 mg 10 mg powder = 500 µg DHE mesylate EXAMPLE 3C (powder) Dihydroergotamine mesylate 0.5 mg β-cyclodextin 5 mg Lactose 4.5 mg 10 mg powder = 500µg DHE mesylate

Claims: A powdered pharmaceutical composition for nasal administration, comprising dihydroergotamine, a dihydroergotamine salt or a combination thereof, and an excipient, wherein the excipient is comprised of cyclodextrin, sugar alcohol or dextran, or any combination thereof, provided that, when a cyclodextrin is present in the pharmaceutical composition, said composition does not include a penetration or absorption promoter, the disruptive effect of which, on lipid membranes, is reduced in the presence of the cyclodextrin. A pharmaceutical composition for nasal administration, comprising dihydroergotamine, a dihydroergotamine salt or a combination thereof, and an excipient, wherein the excipient is comprised of cyclodextrin, or dextran or any combination thereof, provided that, when a cyclodextrin is present in the pharmaceutical composition, said composition does not include a penetration or absorption promoter, the disruptive effect of which, on lipid membranes, is reduced in the presence of the cyclodextrin. A pharmaceutical composition as claimed in claim 2, additionally comprising a sugar alcohol. A powdered pharmaceutical composition for nasal administration, comprising dihydroergotamine, a dihydroergotamine salt or a combination thereof, and an excipient, wherein the excipient is comprised of a sugar alcohol. A pharmaceutical composition as claimed in claim 4, wherein the excipient is further comprised of: i) cyclodextrin; ii) dextran; and/or iii) a saccharide other than cyclodextrin. A pharmaceutical composition for nasal administration, consisting of dihydroergotamine, a dihydroergotamine salt or a combination thereof, and an excipient, wherein the excipient consists of cyclodextrin, sugar alcohol or dextran, or any combination thereof. A pharmaceutical composition for nasal administration, consisting of dihydroergotamine, a dihydroergotamine salt or a combination thereof, and an excipient, wherein the excipient consists of cyclodextrin, dextran or any combination thereof, and optionally sugar alcohol. A pharmaceutical composition as claimed in any of claims 1 or 3 to 7, wherein the sugar alcohol is mannitol, sorbitol or a mixture thereof. A pharmaceutical composition as claimed in any of claims 2 to 8 in powder form. A pharmaceutical composition as claimed in claims 1 or 9 in freeze dried powder form. A pharmaceutical composition as claimed in any of claims 1, 9 or 10, wherein the particles of the powder have a diameter between 50 and 100 µm. A pharmaceutical composition as claimed in any of claims 1 to 11, wherein the dihydroergotamine salt is dihydroergotamine mesylate, dihydroergotamine tartrate or a mixture thereof. A pharmaceutical composition as claimed in any of claims 1 to 12, wherein said excipient consists of, or is comprised of, cyclodextrin or dextran. A pharmaceutical composition as claimed in any of the preceding claims, wherein said excipient consists of, or is comprised of, one or more cyclodextrin. A pharmaceutical composition as claimed in any of claims 1 to 14, wherein the cyclodextrin is an α-, β- or γ-cyclodextrin, a derivative of an α-, β- or γ-cyclodextrin or a mixture thereof. A pharmaceutical composition as claimed in any of claims 1 to 15, wherein the cyclodextrin is a β-cyclodextrin, a derivative of a β-cyclodextrin or a mixture thereof. A pharmaceutical composition as claimed in claim 15 or 16, wherein the derivative of β-cyclodextrin comprises a methylated β-cyclodextrin with a degree of substitution between 0.5 and 3.0. A pharmaceutical composition as claimed in any of the preceding claims, wherein said excipient consists of, or is comprised of, one or more dextran. A pharmaceutical composition as claimed in any of the preceding claims, wherein the dextran has an average molecular weight between 10,000 and 100,000, preferably between 40,000 and 70,000. A process for preparing a pharmaceutical composition as claimed in any of the preceding claims, comprising combining a dihydroergotamine, a dihydroergotamine salt or a combination thereof with the excipient. Use of dihydroergotamine, or a salt thereof, in the preparation of a medicament for the treatment of migraine attacks by administering the medicament to the nasal mucosa, wherein the medicament comprises a pharmaceutical composition as claimed in any of claims 1 to 19.

Inventors: MERKUS FRANCISCUS WILHELMUS HE, MERKUS, FRANCISCUS WILHELMUS HENRICUS MARIA
Applicants: MERKUS FRANCISCUS WILHELMUS HE, MERKUS, FRANCISCUS WILHELMUS HENRICUS MARIA
Application year: 1994
Main classification: A61K31
IPC codes: A61K47, A61K9